Design of Drug Dosage Regimen for Valproate: Exploring Modeling and Simulation Based Approach

Background: Population pharmacokinetic studies attempt to explain the variability in pharmacokinetics among study subjects and explore the role of covariates on the pharmacokinetics. The present study was planned to evaluate by simulation, the various dosage regimens of valproate and their predicted relevance to achieve desired therapeutic ranges and to see the effect of various covariates. Materials and Methods: This study utilized the previous database of therapeutic drug monitoring data of valproate available in the department and population pharmacokinetic models developed by a group in the department. From the database, 93 patients’ details have been used in this study. The simulation studies were carried out for various dosage regimens such as 400mgQ12Hr, 500mgQ12Hr, 800mgQ12Hr, 1000mgQ24Hr for 100 simulated patients using NON-MEM software package. Results: 500mg BID dosage regimen was found to be more advantageous as more number of simulated patients were having the C_ss within the therapeutic range and the effect of covariates like sex and concomitant phenytoin use were found to be insignificant but with 1000mg OD regimen in females, the number of individuals with C_ss within the therapeutic range were found to be less with which we could say that the induction effect of phenytoin on valproate metabolism in females could be more than that of males. Conclusion: The present study was able to predict steady state concentrations for various dosage regimen scenarios with possible pharmacokinetic and therapeutic outcomes. This study underscores the relevance of population pharma-cokinetic based simulations in dosage regimen design.